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New anti-cancer characteristics of jatrophane diterpenes from Euphorbia dendroides
Ist Teil von
Food and chemical toxicology, 2011-12, Vol.49 (12), p.3165-3173
Ort / Verlag
Oxford: Elsevier Ltd
Erscheinungsjahr
2011
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
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► Jatrophanes from Euphorbia dendroides are potent multi-drug resistance modulators that are non-toxic for normal cells. ► Jatrophanes are successful in sensitization of multi-drug resistant cancer cells to paclitaxel. ► Synergy between jatrophanes and paclitaxel is followed by G2M arrest, cell death and anti-angiogenic activities.
Jatrophane diterpenes were shown to be inhibitors of P-glycoprotein (P-gp). There are also evidences on their microtubule-interacting activity in cancer cells. We evaluated new anti-cancer characteristics of two jatrophane type compounds from Euphorbia dendroides. For that purpose, the model system of sensitive non-small cell lung cancer cell line (NCI-H460) and its resistant counterpart (NCI-H460/R) was used. Although both jatrophanes showed inhibitory effect on cancer cell growth, they were non-toxic for peripheral blood mononuclear cells (PBMC). We examined their effects in combination with paclitaxel (PTX), a well-known mitotic spindle interacting chemotherapeutic. Jatrophanes overcome PTX resistance in concentration-dependent manner in MDR cancer cell line (NCI-H460/R). We observed that this synergistic effect is not caused merely by P-gp inhibition. In combination with PTX, jatrophanes induce cell killing and change cell cycle distribution leading to G2/M arrest. Furthermore, they exert an anti-angiogenic effect by decreasing the vascular endothelial growth factor (VEGF) secretion. The reduction of the level of mdr1 mRNA expression in sensitive cells, suggests that these compounds could not contribute to the development of resistance. In conclusion, present study provides a rational basis for the new cancer treatment approach with jatrophanes that are non-toxic to normal cells and have new favorable anti-cancer characteristics.